Live-attenuated vectors based on recombinant vesicular stomatitis virus (VSV) expressing Env and Gag proteins are effective vaccines that have provided solid protection against AIDS in a rhesus macaque model. Although the VSV-based vaccine has been 100% effective to date, all vaccinated monkeys became infected with the challenge virus and showed significant decreases in CD4 T cell counts before viral loads were controlled to levels below detection. In vaccine studies using other vector systems or other challenge models, there have been vaccine failures. These failures appear to result from viral evasion of the immune response through mutation of epitopes recognized by cytotoxic T lymphocytes (CTL). These vaccine failures underscore the need to diversify the CTL responses and to activate CTL under conditions that will generate an optimal CTL memory population. The studies proposed here are designed to optimize and broaden the memory CTL responses to HIV/SIV proteins generated by VSV vectors. Specifically, new recombinant VSV vectors encoding costimulatory molecules and cytokines, as well as vectors optimized for generating higher levels of antigen in infected cells will be developed and tested. In addition, vectors expressing SIV early proteins and Vif will be developed. The efficiency of primary and memory CTL induction with these new vectors will be assessed using several methods in a mouse model, and promising strategies will subsequently be moved into monkey studies. Although an effective AIDS vaccine based solely on generation of T cell responses may be developed, an ideal vaccine would also generate a broad neutralizing antibody response and prevent the initial infection. The second part of this proposal is therefore targeted toward a novel approach of developing VSV G protein to display neutralizing epitopes of HIV in high density on the surface of recombinant virus particles. The ability of such particles to induce neutralizing antibodies to HIV will be studied.